ES2261469T5 - Process to produce micro and / or nanoparticles - Google Patents

Abstract

A process and an apparatus are proposed to perform the supercritical assisted atomization of nano and/or micro metric powders. It is possible to use liquid solvent at process conditions in which they show a low solubility in carbon dioxide. Atomization is obtained by solubilizing pressurized carbon dioxide (compressed, liquid, supercritical) in a solution formed by the solid to be micronized and the liquid solvent, solubilizing carbon dioxide up to near equilibrium conditions and then atomizing the solution down to near atmospheric conditions through a thin wall injector, to produce very small droplet of micronic and sub-micronic dimensions. The subsequent evaporation of the droplets produces particles with diameters ranging between 0.02 and 10 micron.

Description

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DESCRIPTION

Process for producing micro and / or nanoparticles Field of the invention

[0001] This invention is particularly suitable for processing solids that are soluble in liquid solvents with boiling temperatures below about 120 ° C and not thermolabile at process temperatures of up to about 80 ° C, to produce such solids in the form of micro and nanoparticles with dimensions ranging between 0.01 and 100 microns. A non-exhaustive list of the different industrial application fields of solids in the form of micronic powders is: catalysts, metal oxides, coatings and films, cosmetics, electromagnetic components, electronic devices, pigments, ceramic compounds, toners, polishing products, retarding materials of llamas, biopolymers, polymeric compounds and drugs.

State of the art in the field of the described invention

[0002] During the last fifteen years several techniques and devices have been proposed to produce powders, based on the use of compressed gases and / or in supercritical conditions. In many cases carbon dioxide has been proposed as the process fluid. The different techniques described in the technical and patent literature can be organized into three main areas and schematized as follows:

Rapid Expansion of Supercritical Solutions (RESS). This process is based on the solubilization of the solid that must be micronized in a supercritical solvent and subsequent depressurization until the atmospheric pressure approximates that of the solution formed and the precipitation of the solute. Many variations of this process and related devices have been proposed: DE 2943267, US 4582831, US 4734451, US 4970093.

Its most important limitation is the limited solubility of many solids in the supercritical solvent. The morphology and particle size control is also very complex.

[0003] The precipitation of a liquid solution induced by a supercritical antisolvent (several acronyms ASES, SEDS, GAS and SAS have been used) we will refer to this technique as SAS (supercritical antisolvent precipitation) hereinafter. This technique will be referred to as SAS (supercritical antisolvent precipitation) hereafter This technique has been described in detail in "Supercritical antisolvent precipitation of micro and nano particles, Reverchon, 1999, J. Supercrit. Fluids, 15; 1-21. Preconditions for the application of this process are that the solvent Kqido is completely soluble in the supercritical antisolvent, while the solid is completely insoluble in this, however, the SAS processability of many solids is problematic, but in cases where that the micronization has been carried out successfully, a fair control of the morphology and the sizes of the particles has been obtained (varying from submicron to particles of hundreds of microns). Also in this case the patent bibliography contains many processes and variations It is interesting, for example, the variation proposed by Hanna and York that used some different devices of coaxial injectors for to the simultaneous mixing and atomization of the supercritical antisolvent and the liquid solution (acting in this way it is possible to obtain a mechanical contribution to the formation of particles due to the speed of the two flows at the outlet of the injector). The patents presented in the literature differ by the application or by the fluids used (as examples, the use of an organic solvent and a supercritical solvent, or solvent and antisolvent both under supercritical conditions, or a liquid solution a second solvent is proposed and a supercritical antisolvent - US 6063138) or small variations of the apparatus are proposed to optimize its use in the micronization of different substances.

[0004] Generation of Gas Saturated Solutions Particles (PGSS). In this field the patent deposited by Weidner and Knez (EP 744992, WO 9521688) that proposed the use of supercritical carbon dioxide to be solubilized in molten polymers in a heated vessel is explicitly located. Supercritical carbon dioxide solubilizes in large quantities in many polymers that also induce its liquefaction (due to the reduction of the glass transition temperature). The polymer solution obtained in this way is sent to an injector and sprayed in a container operated at a lower pressure, forming polymer droplets that return to the solid state due to the cooling induced by carbon dioxide. The minimum documented diameter of the particles produced by this technique is 7.8 microns.

The processes that have many similarities with the PGSS are many spray coating processes proposed in the patent literature (US 5057342, US 5066522, US 5009367, US 5106650, US 5211342, US 5374305, US 5466490), although the purpose of this The process is different from that of the present invention and is to produce very small droplets of coloring matter to improve the performance of the coatings. The supercritical fluid in this case is used to reduce the viscosity of the solution to be sprayed. Another feature that is claimed in these patents is the reduction or elimination of volatile organic compounds (VOC). In some of these patents the same process is proposed to produce powders by spraying.

Another process that in certain aspects is related to the PGSS is that proposed by Sievers et al. (EP 677332, US 5639441, US 6095134). These authors propose a process where an aqueous solution and a flow of carbon dioxide are brought into contact in a low-volume T-element (with an internal volume of less than 1 microliter). The immiscible mixture of the liquid and the supercritical fluid (defined by the authors a suspension, an emulsion, a micellar system or a dispersion) is sent to a capillary nozzle (a long thin tube

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with an internal diameter of, for example, 125 microns), very small droplets are formed that evaporate and produce a powder. The examples proposed in patents and scientific documents published by the authors are restricted to the use of water as a liquid solvent. Also US-B-6 221 153 describes a process where the solution containing the target substance is brought into contact with the pressurized CO2 stream inside the tube before reaching the expansion chamber. Ventosa et al. described (Crystal Growth or Design, 2001, Vol. 1, No. 4, pages 299-303) a process for preparing nanoparticles comprising the solubility of the solid in an organic solvent, the solubility of carbon dioxide in this solution and the injection of the solution in a precipitation vessel.

[0005] The new process that is proposed in the present invention refers, instead, to the formation of solutions formed by carbon dioxide and liquid solvents where the solute is solubilized and for subsequent atomization. The formation of the liquid solution containing carbon dioxide is regulated by the thermodynamics of pressurized fluids and by the connected liquid vapor equilibria, and is not related to the heating and melting of solids. Virtually all liquid solvents can be used and smaller particles can be produced than can be obtained with the previous patented processes.

Description of the invention

[0006] The invention consists of a new and more efficient process according to revindication 1 and an apparatus for executing carbon dioxide assisted atomization to produce nanometric and micrometric particles. Using this process and the proposed apparatus it is possible to control the average size of the particles and the distribution of the size of the particles; with the unexpected possibility of obtaining average diameters between approximately 0.01 (10 nanometers) and 100 microns that had never before been obtained using processes based on the use of supercritical fluids. Due to the wide range of operating conditions and the possibility of producing particles with an average diameter included in a wide range of dimensions, using this invention it will be possible to:

- replace many of the existing micronization processes based on the use of organic solvents;

- operate using the same device either using organic solvents or using water, thus expanding the range of applicability of techniques previously described in the literature.

[0007] Carbon dioxide is solubilized in a liquid solution (formed by one or more solvents containing a solid solute) in a fixed bed (saturator) formed by a vessel capable of operating under pressure. The carbon dioxide could be compressed, liquid or supercritical. A preferred requirement is that under the process conditions the liquid solvent or solvent mixture show a low solubility in carbon dioxide.

[0008] The saturator is loaded with metal or ceramic fillings (for example, Rashig rings or perforated chairs) with the aim of obtaining a large contact area between the liquid and the gas and, thus, favoring the dissolution of gas in the liquid. The objective is to dissolve carbon dioxide in the liquid to concentrations close to the equilibrium of the solubility, under the operating conditions of pressure and temperature.

[0009] The amount of carbon dioxide that can be dissolved in the liquid, under the operating conditions, can be between 0.01 and about 0.50, preferably between 0.02 and 0.2, in terms of molar fractions. However, carbon dioxide can be added in amounts slightly larger than the expected equilibrium values due to the uncertainty in these values and to ensure that the maximum amount of carbon dioxide is dissolved in the liquid (thus maximizing the process performance ).

[0010] A solution is obtained, formed by a liquid phase containing the solid solute and carbon dioxide.

[0011] This solution is atomized through a wall injector that has one or more holes and is depressurized to nearby atmospheric conditions. Working this way, micronic and / or submicronic droplets are formed, which quickly vaporize on the precipitator placed under the injector. This operation is supported by the heating of the precipitator and by the use of a stream of heated inert gas (nitrogen, argon, air) added to the precipitation chamber.

[0012] The solid particles produced by evaporation of the Kquido droplets are forced to move through the precipitator and are collected at the bottom; while, inert gas, liquid vapors and carbon dioxide are sent to a separator for the recovery of the liquid and to be carried out by cooling and recompression of the CO2 can be added (closed loop operation).

[0013] The key parts of the apparatus for a successful treatment and the production of particles as claimed in the present invention are the parts in all possible process combinations:

a) saturator containing fillers that ensure contact and balance between phases;

b) a thin wall injector with hole diameters between 10 and 500 microns, preferably between 20 and 200 microns.

c) a flow conveyor, placed inside the precipitator that prints a spiral direction to the gas + dust in the precipitator and favors the deposition of dust at the bottom of the precipitation chamber.

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The powders obtained using the described method can be amorphous or crystalline depending on the characteristics of the solute, the solvent used and the process conditions during precipitation.

Description of the figures

[0014]

Figure 1: schematic representation of the device

Figure 2: Image of the scanning electron microscope (SEM) of micronized yttrium acetate.

Figure 3: Distribution curve of particle size related to Figure 2.

Figure 4: SEM image of micronized Prednisolone.

[0015] In Figure 1 three parallel ducts are drawn and indicated with the numbers 1, 2 and 3 and related to the delivery of inert gas, carbon dioxide and liquid solution, respectively.

In conduit 1:

St1: Inert gas storage container; M1: Manometer; S1: heat exchanges, with thermal regulation system, T1;

In conduit 2:

St2: Carbon dioxide storage container; S2: First thermostated bath for carbon dioxide (refrigerator); P2: Pump; S2-1: Second thermostated bath for carbon dioxide (heater).

In conduit 3:

St3: Liquid solution storage container; P3: Pump; S3: Thermostated bath (heater).

[0016] Other parts of the apparatus are: Sat: Saturator, and the related thermal regulation system T; Lp (a): Septum injector; Pr: Precipitator (dust collection chamber), and the related thermal regulation system T; internal pressure regulation system (M: Manometer + check valve), cf: Flow conveyor; Sr: cooled separator; C: dry test meter.

[0017] The SEM image of Figure 2 has been taken at a magnification of 15000x.

[0018] From the SEM image (in figure 2) it is possible to obtain the particle size distribution (Figure 3) using an image analysis software. This distribution is provided as a histogram:% of particles vs particle diameter. Minimum diameter 0.02 microns; maximum diameter: 0.72 microns.

[0019] The SEM image of Figure 4 has been taken at a magnification of 10000x.

Detailed description of the device and the process scheme

[0020] The apparatus used in the present invention contains two pressure lines used to deliver: the Kqida Lq solution and the compressed gas, Kgido or supercritical Lg. The third conduit operates at pressures close to the atmosphere and delivers a heated gas to favor the evaporation of liquid in the precipitator.

The liquid line Lq is formed by a storage container St3 containing the solution (liquid + solute) connected to a high pressure dosing pump P3 that can deliver a constant flow of liquid up to an operating pressure of 350 bar. The liquid is sent to an S3 heat exchanger in which it is preheated to temperatures between 50 and 90 ° C and then to the Sat.

The flow of carbon dioxide, compressed, liquid or supercritical, is obtained by delivering carbon dioxide from a storage tank to a high pressure dosing pump that has been modified to allow the use of compressible fluids and that can deliver constant flows of carbon dioxide up to an operating pressure of 350 bar. Carbon dioxide passes through an S2-1 heat exchanger to be heated to temperatures between 40 and 90 ° C, then it is sent to the Sat.

The two flows (liquid solution and carbon dioxide) are mixed in the Sat saturator, which is formed by a thermostated tank that can operate up to 350 bar and is loaded with the appropriate filling elements, for example, Rashig rings, perforated chairs or organized fillings, whose objective is to ensure prolonged contact between the two phases (liquid and dense gas).

The saturator guarantees a large surface area and sufficient contact time to allow solubilization of carbon dioxide in the liquid until equilibrium conditions are close to operating temperature and pressure. However, a slight excess of carbon dioxide can be used with respect to the expected equilibrium value to ensure obtaining saturation conditions.

The solution formed in the saturator is sent to the thin-wall injector that connects the saturator and the precipitator (dust collection chamber) that operates at pressures close to the atmosphere under reduced pressure.

[0021] The Ip thin wall injector is formed by one or more holes having diameters ranging between 20 and 200 microns made in a thin stainless steel wall. This kind of injector concentrates all the pressure drop (pressure difference) between the saturator and the precipitator at the point of injection to obtain an effective pulverization. The pulverization will be formed by very small droplets. The average diameter of the droplets

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formed will be particularly small since, we think that carbon dioxide during atomization eliminates the liquid phase in which it was dissolved (decompressible atomization).

The precipitation chamber Pr is a thermostated cylindrical vessel where, in addition to carbon dioxide and the liquid solution, hot inert gas (nitrogen, argon, air) is delivered at the same time after preheating in a S1 heat exchanger up to 100 ° C; The objective is to shorten the evaporation process of the droplets.

The solid particles that are formed as a result of the liquid evaporation move together with the gas in the precipitator and form a two-phase flow (for example: Dust, carbon dioxide, nitrogen and vapors of the liquid solvent) going to the bottom of the precipitator by the Cf helical flow conveyor inserted in the chamber.

The flow conveyor Cf is formed, for example, by a metal propeller that prints an orderly movement to the gases of the solid + mixture. This allows the exit of the gases from the bottom of the precipitator and the collection of the powder in a sintered stainless steel material, arranged at the bottom of the precipitator. Alternatively, electrostatic dust collection is possible.

The gases at the outlet of the precipitator are sent to a cooled separator Sr placed below the precipitator, where the liquid solvent K is condensed and recovered while; the remaining gaseous mixture: it is discharged at the outlet of the device.

Flow meters, temperature and pressure indicators and temperature controllers complete the device.

Examples

Example 1

[0022] Production of yttrium acetate nanoparticles (a superconducting precursor - Acy) by precipitation of a solution with Methanol with a concentration between 2 and 50 mg of AcY / ml of Methanol (preferably, varying between 15 and 25 mg of AcY / mg Methanol) using the carbon dioxide-assisted atomization process described in the present invention; at pressures between 80 and 140 bar (preferably, between 85 and 100 bar) and at temperatures ranging between 60 and 95 ° C (preferably, between 65 and 80 ° C). We use a thin-wall injector with a diameter between 60 and 100 microns (preferably 80 microns) with a single hole. The flow rate of the liquid solution can vary between 1 and 7 g / min (preferably, 3 g / min); the flow rate of carbon dioxide can vary between 3 and 12 g / min (preferably, 6.5 g / min). An example of the produced nanoparticles is provided in Figure 2, where an SEM image of AcY particles is proposed. The particles obtained are spherical, amorphous and their average diameter and particle size distribution are provided in Figure 3.

Example 2

[0023] Production of micronic diphenylhydantoin particles by precipitation of a methanol solution for concentrations between 2 and 15 mg of diphenylhydantoin / ml of methanol, using the carbon dioxide assisted atomization process described in the present invention; at pressures between 75 and 120 bar (preferably between 90 and 100 bar) and at temperatures between 60 and 95 ° C (preferably, between 65 and 75 ° C). We use a thin-wall injector with a diameter between 60 and 100 microns (preferably 80 microns) with a single hole. The flow rate of the liquid solution may vary between 2 and 10 g / min (preferably, 4 g / min); The carbon dioxide flow rate can vary between

3 and 10 g / min (preferably, 7 g / min). The resulting particles are spherical and their average diameter varies between 0.8 and 2.5 microns.

Example 3

[0024] Production of microcrystals of Nifedipine by precipitation of a solution with Acetone for concentrations between 2 and 150 mg of Nifedipine / ml of Acetone, using the carbon dioxide-assisted atomization process described in the present invention; at pressures between 60 and 80 bar (preferably between 60 and 70 bar) and at temperatures between 70 and 100 ° C (preferably, between 70 and 80 ° C). We use a thin-wall injector with a diameter between 60 and 100 microns (preferably 80 microns) with a single hole. The flow rate of the liquid solution may vary between 2 and 9 g / min (preferably, 5 g / min); The carbon dioxide flow rate can vary between

4 and 14 g / min (preferably, 9 g / min). Its average diameter varies between 1 and 5 microns.

Example 4

[0025] Production of rifampicin microparticles by precipitation of a solution with Alcohol for concentrations between 2 and 30 mg of Rifampicin / ml of Alcohol, using the carbon dioxide-assisted atomization process described in the present invention; at pressures between 80 and 130 bar (preferably between 90 and 105bar) and at temperatures between 50 and 80 ° C (preferably, between 50 and 60 ° C). We use a thin-wall injector with a diameter between 60 and 100 microns (preferably 80 microns) with a single hole. The flow rate of the liquid solution may vary between 2 and 9 g / min (preferably, 5 g / min); The carbon dioxide flow rate can vary between 4 and 14 g / min (preferably, 8 g / min). The resulting particles are amorphous, spherical and their average diameter varies between 0.5 and 2.0 microns.

Example 5

[0026] Production of Prednisolone microparticles by precipitation of a solution with Methanol for concentrations between 1 and 65 mg of Prednisolone / ml of Methanol, (preferably, between 3 and 50 mg / ml of Methanol) using the dioxide-assisted atomization process carbon described in the present invention; at pressures 5 between 80 and 120 and at temperatures between 60 and 85 ° C. We use a thin-wall injector with a diameter between 60 and 100 microns (preferably 80 microns) with a single hole. The flow rate of the liquid solution may vary between 5 and 15 g / min (preferably, 8 g / min); The carbon dioxide flow rate can vary between 2 and 8 g / min (preferably, 3 g / min). An example of microparticles obtained using the described process is provided in Figure 4, where an SEM image of prednisolone particles is shown. These particles have been obtained operating at 10 98 bar, 71 ° C and 45 mg / ml Methanol; These are spherical, amorphous and their average diameter is 1.1 microns.

Claims (11)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 65 1. Process to produce micro and / or nano solids particles with an average diameter between 0.01 and 100 micrometers, a process that includes the steps of: - solubilization of the solid in a liquid solvent or a mixture of liquid solvents, where the liquid solvent or the mixture of liquid solvents has a very low or zero solubility in carbon dioxide under conditions with a temperature between 40 and 90 ° C and a pressure between 50 and 240 bar; - solubilization of dense carbon dioxide in the liquid solvent or the mixture of liquid solvents, the carbon dioxide being supercritical, where the solubilization takes place in a saturation chamber (sat) loaded with large surface fillings at process conditions with a temperature value between 40 and 9 0 ° C and a pressure value between 50 and 240 bar; - injection of the solution thus obtained through a thin-walled injector (Ip) into a precipitation vessel (Pr) operated at a pressure value close to atmospheric pressure; Y - delivery of a flow of inert gas heated to 100 ° C inside the precipitation vessel to allow nano and / or solid micro particles to be formed by evaporation of droplets; Y - recovery of the dusts produced. 2. Process according to claim 1, wherein the process conditions are between 40 and 90 ° C and 60 and 150 bar, giving particles with an average diameter between 0.02 and 10 micrometers. 3. Process according to any of the preceding claims, wherein a solid solute consisting of more than one compound is used, in order to obtain an extremely uniform coprecipitate. 4. Process according to any of the preceding claims, wherein the liquid solvent K is selected from the group consisting of Methanol, ethyl alcohol, propyl alcohol, acetone, dichloromethane, chloroform and water, or is a mixture of two or more elements of said group in any proportion. 5. Process according to any of claims 1-4, wherein the solid is chosen from the group consisting of categories of solid compounds, for example, active ingredients for pharmacological use, active ingredients for veterinary use, superconductor precursors and catalyst precursors . 6. Process according to any of claims 1-4. where the solid is chosen from the group consisting of powders that are usable in injectable suspensions, atomizable powders, transdermal formulations and controlled release formulations, with particular reference to antibiotics, enzymes, asthma control drugs, preferably corticosteroids, chemotherapies and anti-inflammatory 7. Process according to any of claims 1-4, wherein the solid is chosen from the group consisting of ceramics, phosphors, toners, cosmetics, conductive pastes, explosives, propellants, flame retardants, polymeric compounds, pigments, polymers and metal oxides. 8. Apparatus for carrying out the process according to any of the preceding claims, comprising: a saturator (Sat) loaded with fillers, a precipitator (Pr), a thin-walled injector (Ip) that connects the saturator (Sat) and the precipitator (Pr), for the formation of droplets, a first pressure line (Lq) to deliver a liquid solution to a first thermal exchanger (S3) for preheating the liquid solution at temperatures between 50 and 90 ° C, and subsequently to the saturator (Sat), a second pressure line (Lg) for delivering dense carbon dioxide to a second thermal exchanger (S2-1) for heating dense carbon dioxide at temperatures between 40 and 90 ° C, and subsequently to the saturator (Sat), and a third pressure duct that operates at pressures close to the atmospheric value to deliver an inert gas to a third thermal exchanger (S1) for preheating the inert gas to 100 ° C, and subsequently to the precipitator (Pr). 9. Apparatus according to claim 8, wherein the thin wall injector (Ip) has holes with diameters between 10 and 500 micrometers. 10. Apparatus according to claim 8 or 9, wherein said fillers are metallic or ceramic such as Raschig rings or perforated chairs. 11. Apparatus according to any of claims 8-10, which further comprises a flow conveyor (Cf) to favor the collection of the dusts produced.